Project Summary Natural products have served as a productive source of drugs over the past decades and have represented, or been the inspiration for, a majority of antimicrobial compounds that have entered the clinic. The goal of this proposal is to develop novel antibacterial adjuvants based on the marine natural product synoxazolidinone B to treat Gram-positive orthopedic joint infections. These scaffolds have the potential to clear biofilm-implicated recalcitrant infections based on preliminary in-vitro data. These biofilm-implicated infections are tolerant to traditional antibiotics and represent a significant clinical need since up to 80% of human infections involve biofilm-associated microorganisms. Few small molecules have been isolated that have the potential to disrupt biofilms, thereby functioning to clear biofilm associated infections. Herein, we propose to develop a class of compounds that is capable to addressing the treatment of biofilm associated infections and generate the key data necessary for a go/no-go decision to advance these molecules toward a Phase II pre-clinical study.